THE DECOMPENSATED MONOFIXATION SYNDROME (AN AMERICAN OPHTHALMOLOGICAL SOCIETY THESIS)

Transcription

1 THE DECOMPENSATED MONOFIXATION SYNDROME (AN AMERICAN OPHTHALMOLOGICAL SOCIETY THESIS) BY R. Michael Siatkowski MD ABSTRACT Purpose: To describe the clinical features and response to treatment of patients with decompensated monofixation syndrome (MFS) and to propose a hypothesis for a decompensation mechanism in such patients. Methods: Fourteen adults with MFS who had been symptomatically stable for a mean duration of 25 years developed diplopia in the absence of neurologic or orbital disease. After retrospective chart review, they underwent detailed orthoptic testing. Results from this cross-sectional analysis were compared with similar data from 16 control subjects with stable MFS. Results: Compared to stable MFS patients, decompensated subjects had significantly poorer horizontal fusional amplitudes but greater torsional fusional amplitudes; they were also more likely to have a small vertical strabismus and to have received initial treatment later. Stable subjects, however, also had subnormal horizontal as well as torsional fusional amplitudes. There was no difference between groups with respect to refractive error, amblyopia, type or prior treatment of strabismus, stereoacuity, or angle of deviation. After treatment, all patients regained monofixational alignment, but up to one-third had continued diplopia. Symptoms recurred in two patients whose treatment was initially successful. Conclusions: Patients with MFS lose fusional amplitudes over time. In some cases this results in development of sensory torsion with secondary decompensation and diplopia. The rate of decompensation averages 7% per year from ages 20 to 70. Treatment for decompensation offers excellent motor results, but sensory symptoms may persist and recurrent symptoms may develop. Monitoring and maintenance of fusional vergence amplitudes should be part of the routine care for patients with MFS. Trans Am Ophthalmol Soc 2011;109: INTRODUCTION That some type of sensory adaptation is required in response to strabismus was first recognized almost three centuries ago by de la Hire 1,2 and further considered in the following century by Müller. 3,4 Although erroneous in their assumption that ocular misalignment was due to anatomic displacement of the foveas, and although their musings occurred prior to Wheatstone s initial explanation of normal stereopsis, 5 they laid the foundation for our current understandings of the objective and subjective changes that are present in individuals with abnormal binocular function. Today we recognize the spectrum of binocular interaction as ranging from constant bifoveation at one end to complete monocularity at the other. Of particular interest is the subset of persons with either straight or almost-straight eyes but subnormal fusion and/or stereopsis. Although Pugh 6 first called attention to these small-angle deviations in 1936, work on this condition began in earnest in 1951, when Jampolsky 7 commented on patients with small-angle esotropia and retinal slip. Gittoes-Davies 8 and Levinge 9 referred to such patients in terms of fixation disparity, and Bryer 10 called the small shift seen on alternate cover testing flick, hence the term flicker cases. In 1955 Lyle and Foley 11 noted that subjects with very small degrees of strabismus could possess excellent peripheral fusion. In 1956 Jampolsky 12 called attention to additional clinical characteristics of these patients. He noted that they often had phorias much larger than their manifest deviations and first postulated that their degree of ocular misalignment was sufficiently small as to permit the development of normal retinal correspondence (NRC). He also noted that despite intensive orthoptic therapy, these patients were incapable of achieving completely normal binocular function and high-grade stereopsis. Six years later, Jampolsky 13 used the phrase fusion with disparity in fixation (later shortened to fusion disparity but also sometimes fixation disparity ) to refer to patients with 6 to 10 minutes of arc deviation but in whom both maculas were capable of simultaneously functioning. He also used the phrase heterophoria without bifoveation to describe the phenomenon of patients with very small-angle ocular misalignment and peripheral fusion but inability to use both foveas simultaneously. It is worth noting that while the term fixation disparity is found throughout a wide range of literature in association with patients with small-angle strabismus and deficient stereoacuity, it was originally used in 1949 by Ogle 14 in the context of normal binocular function. The term originally applied to the small levels of imprecision in the intersection of the visual axes while viewing any object of interest. Thus a term originally intended to describe normal visual physiology has been incorrectly used to refer to subjects with small degrees of strabismus and remains, unfortunately, indelibly corrupted. The fixation disparity issue notwithstanding, further work in the 1960s, important and novel as it was, intensified the semantic dilemmas encountered in the literature on this topic. In 1961 Parks 15 coined the phrase monofixational phoria to describe patients with a small manifest deviation and a much larger heterophoria uncovered by prolonged alternate cover testing. This term was used by others for several years 16,17 but criticized by Lang 18 due to the presence of a manifest tropia as well as the fact that some of these patients clearly demonstrated anomalous retinal correspondence (ARC). He offered the term microtropia unilateralis anomalofusionalis, also known as microtropia or microstrabismus. Microtropia was also the title of Helveston and von Noorden s 1967 article, 19 which they subtitled A Newly Defined Entity to connote the subset of patients with strabismus so small as to be undetectable by cover testing; they noted that anisometropia was present in a large majority of such cases. In 1973 Epstein and From the Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma College of Medicine, Oklahoma City. Trans Am Ophthalmol Soc / 109 /

2 Siatkowski Tredici 20 evaluated a similar condition in aviation personnel, interspersing the terms monofixation syndrome and microtropia in their title and suggesting that stereoacuity of 40 arc seconds was possible in either. The1969 American Ophthalmological Society (AOS) thesis of Marshall Parks, The Monofixation Syndrome, 21 represents the culmination of work performed and concepts refined over the preceding two decades, and his organized description remains the most widely cited today. Unfortunately, imprecision in verbiage persists. Even the American Academy of Ophthalmology s Basic and Clinical Science Course text intersperses both monofixation syndrome with microtropia, prompting some to suggest that additional terms such as minitropia, macro-microtropia, and true microtropia could bring clarity (!) to the situation. 22 As this author considers the thesis of Parks to be the seminal work in the description and classification of this condition, it is his definition of monofixation syndrome (MFS) that will be used in this manuscript. Parks recognized four possible etiologies of MFS: previously treated strabismus (the most common cause), anisometropia without strabismus, a unilateral macular lesion, and primary or idiopathic (no history of prior strabismus or strabismus treatment, anisometropia, or maculopathy). His 1969 criteria for the diagnosis of MFS include the following constant attributes: a horizontal strabismus of no more than 8 prism diopters (PD), orthophoria being possible and esodeviations much more common than exodeviations; facultative suppression of the nonfixating eye under binocular viewing conditions; good fusional vergence amplitudes; and inability to convert to bifoveation despite any form of treatment. The following additional clinical attributes occur variably: amblyopia and manifest strabismus (each in approximately three-quarters of cases), large phorias on alternate cover testing, and the presence of measurable stereopsis, but not better than 60 arc seconds. The clinical profile of MFS as described by Parks has been strongly affirmed by the elegant neurophysiological work of Tyschen. 23 Using the macaque monkey, Tyschen demonstrated that a neuron in area V1 of the visual cortex could join receptive fields up to a maximum of 2.5 degrees (4.4 PD); thus two adjacent neurons could join fields up to 5 degrees, or 8.7 PD, apart, corresponding very closely to the Parks rule of a horizontal deviation of not more than 8 PD. Excellent fusional vergence amplitudes can develop, since beyond the region of foveolar suppression the excitatory binocular horizontal neuronal connections in V1 are intact. Thus patients whose horizontal ocular alignment is within 8 PD have the capacity to develop cortical fusion mediated by ocular dominance columns (and receptive fields) separated by up to two axonal lengths; this then is the neural substrate of the clinical state that Parks termed MFS several decades earlier. In the 40 years that have passed since Parks published his thesis, 21 relatively few new clinically based insights into MFS have surfaced. Choi and Isenberg 24 established that up to 6 PD of vertical deviation is compatible with the original description of Parks, and Scott and colleagues 25 postulated primary MFS as a forme fruste or incomplete phenotypic expression of infantile esotropia, since it was found in 6% of parents of children with infantile esotropia. Additionally, in 1996 Harwerth and colleagues 26 reported a possible animal model for MFS in macaque monkeys, by surgically inducing esotropia during the critical period of visual development, and subsequently realigning the eyes. One facet of MFS about which Parks was adamant is its long-term prognosis, namely, the stability of the condition. Parks was quite firm in his conviction that monofixation, once established, did not change. His AOS thesis contains the following statements (italics added): The monofixators are symptomless, cosmetically straight, and tend to remain unchanged with increasing age. The most impressive prognostic feature of patients with the monofixation syndrome is their static alignment state. Over the years their eyes continue to remain aligned as well as if they were bifixating....these data reveal the tendency for the alignment of the monofixator to persist unchanged over the years, a fact noted by many other contributors to his subject. Peripheral fusion alone seems to be just as effective as the combination of peripheral and central fusion in maintaining straight eyes. Six years later, Parks again stated, Once the monofixation syndrome has evolved, almost invariably it remains unchanged. The patient is comfortable and all concerned are happy with the straightness of the eyes. 27 This author became interested in the stability of MFS upon encountering an unusual case early in practice. The patient was a 58- year-old commercial airline pilot with the chief complaint of intermittent binocular diplopia for 1 year. He had a history of refractive accommodative esotropia, treated with glasses in the first decade of life through his teen years. He remained with cosmetically straight eyes and with no visual symptoms apart from presbyopia in his early 40s until age 57, at which time he began to experience diplopia. His prior evaluation had consisted of examinations by two optometrists, two ophthalmologists, a neurologist, and an internist; five different pairs of prism glasses had been prescribed. In addition, computed tomography, magnetic resonance imaging, and magnetic resonance angiography of the head were performed, as were lumbar puncture and electroencephalogram, all of which were normal. On examination, visual acuity was 20/15 in the right eye and 20/20 in the left eye. Ocular motility was full. Via simultaneous prism-cover testing he had a left esotropia of 8 to 10 PD at distance and near, increasing to 18 PD on alternate cover testing. He could see singly with a 10 PD base-out prism, and contour stereopsis with prism correction was 200 arc seconds. Pupils, visual fields, anterior segment, and dilated fundus examination were normal bilaterally. Cycloplegic refraction was sphere in each eye. Based on prior history and examination, a diagnosis of nonstatic MFS (previously stable MFS in which a change in motor alignment and sensory status occurred), or decompensated MFS, was made. A prism adaptation trial commenced, with which his angle built to 25 PD at distance and 30 PD at near. He underwent strabismus surgery with final alignment of 2 PD of esotropia at distance and near. One year postoperatively, his angle was stable, he was diplopia free, and contour stereopsis measured 80 arc seconds. Following this encounter in the early 1990s, I began to formulate a more precise definition of decompensated MFS for patients who had a history of either primary MFS or MFS secondary to anisometropia or previously treated strabismus and had been symptomatically stable for many years into adulthood. This group of patients, however, at some point began to experience binocular diplopia bothersome enough to seek treatment. In some cases, a change in refractive correction or the addition of bifocals for Trans Am Ophthalmol Soc / 109 /

3 Decompensated Monofixation Syndrome presbyopia solved the problem; in others, however, the etiology and treatment of the new symptoms were more elusive. Some of these patients experienced constant or intermittent diplopia along with a change in their ocular alignment. In others, alignment was stable or not visibly changed from their perspective. A retrospective review of stable vs decompensated cases of MFS was presented at the 1997 North American Neuro-Ophthalmology Society (NANOS) meeting (Ganser GL, et al, NANOS, 1997, Abstract, page 2). This study found that amblyopia was significantly more common in stable cases (48% vs 8%, P=.023, Fisher exact test) and that decompensated subjects tended to be exotropic rather than esotropic, although this trend was not statistically significant. This led to a hypothesis that higher levels of stereoacuity may be protective in preventing against decompensation in patients with MFS. However, a subsequent and larger study (Siatkowski RM, et al, Association for Research in Vision and Ophthalmology, 1997, Abstract B426) found no difference between stable and decompensated MFS patients with respect to angle of strabismus, underlying etiology, or level of stereoacuity. This study measured stereopsis prospectively with both contour and random dot tests; for subjects with less than 3000 arc seconds of stereoacuity, a computer-generated haploscopic display was created that could measure levels of stereopsis up to 10,000 arc seconds. Even with this device, no significant difference in stereoacuity was found between the groups. Several other investigators have commented on long-term instability in patients with small-angle strabismus. Undoubtedly, some of these patients would meet criteria for decompensated MFS, but as these reports are incomplete in their clinical data, exact comparison is rarely possible. In 1974 Lang 28 noted 66 children (part of a larger series) with increasing angles of esotropia. However, 92% of these patients had increasing levels of hyperopia, a high accommodative convergence to accommodation ratio, or both; the remaining 8% had amblyopia. Thus these cases seem to be more parallel to the phenomenon described by Wisnicki, 29 in which primary micro-esotropes or esotropes with an accommodative component develop increasing uncorrected hyperopia causing an increase in their manifest angle. Clarke and Noel 30 also noted an increase in angle of strabismus in patients with small-angle esotropia after extensive patching for amblyopia, presumably due to conversion of a large phoria to a tropia with prolonged disruption of binocularity. These previously described patients have very different characteristics than the adults in this study. In 1989 Arthur and colleagues 31 reported on the long-term stability of ocular alignment in patients with MFS. They found that over a mean period of 17.5 years, 26% of monofixators developed an increase in their horizontal misalignment to greater than 8 PD. Although this study relied on mean survival curves to extrapolate long-term data and included no sensory information, it definitively refutes the concept of long-term stability in these cases. Arthur and colleagues also compared unstable MFS cases to unstable cases of non-mfs strabismic patients (in whom the angle of ocular misalignment was larger than 8 PD). There was no difference between these groups with respect to initial alignment or age at diagnosis, but the MFS patients were surgically aligned earlier than the non- MFS subjects. They also noted a large difference in the mean time to instability (decompensation) between monofixating and nonmonofixating strabismic patients, 32.2 years vs 9.8 years. Thus they did support the notion by Parks that the development of MFS is relatively (but not absolutely) protective against instability in motor angle. Interestingly, in a 1986 presentation at the American Academy of Ophthalmology, Parks noted, Never can the ophthalmologist conclude, regardless of the patients age, that once the treatment has successfully aligned the strabismic eyes they will remain straight. 32 Several years later, Shauly and colleagues 33 reported that between one-fifth and one-fourth of patients with microtropia or small-angle esotropia following surgery for infantile esotropia developed a larger angle over time. However, Rowe 34 noted that in 40 patients who were initially treated for infantile esotropia before 2 years of age, none developed a deviation beyond 10 PD over a mean follow-up period of 7 years (range, 4-10 years). In her excellent 2001 Scobee Memorial Lecture, Arnoldi 35 also reported on long-term motor instability over time in patients with MFS, occurring in approximately one-quarter of small-angle esotropes and almost one-half of small-angle exotropes or hypertropes. She found that motor stability was associated with higher levels of both motor and sensory fusion as well as stereopsis. Instability was correlated with the presence of oblique dysfunction, pattern strabismus, amblyopia, and change in refractive error. However, the incidence of adults with diplopia in her study is not clear, since a change in alignment was the a priori definition of instability. In 2005 Hunt and Keech 36 reported on the deteriorated monofixation syndrome using the Parks diagnostic criteria for the original diagnosis and subsequent development of an angle of strabismus greater than 8 PD as their definition for deterioration. They identified 29 patients from the University of Iowa database, all but one of whom had a history of esotropia. Nine patients (31%) complained of diplopia, and 20 (69%) had a history of amblyopia. All but one patient underwent surgical correction of their deteriorated angle, with 48% regaining MFS status postoperatively. However, 4 of the 9 patients with diplopia continued to experience diplopia after treatment. In the Hunt and Keech series, there was also a trend for patients with diplopia to do more poorly after surgery, that is, not to regain monofixational status. Thus these investigators also clearly demonstrate the capacity for patients with MFS to change with time; however, their work does not include any detailed sensory or psychophysical data that might help to elucidate the etiology of the deterioration. Thus it is clear that the body of literature on this topic, including both my previous work as well as that of others, provides no compelling evidence for a definitive etiology of decompensation in patients with MFS. Given the lack of any reproducible association between decompensation and the gamut of clinical factors routinely evaluated (eg, level of stereopsis, presence of oblique dysfunction or dissociated strabismus, density of amblyopia), consideration of a different causative defect is necessary. Since central (foveal) fusion is by definition impaired in MFS, a reasonable and testable hypothesis is that, despite the statements of Parks to the contrary, peripheral fusion is abnormal in these subjects and is associated with decompensation, diplopia, and a change in strabismus pattern. The purpose of this study was to compare clinical characteristics of adults with stable vs decompensated MFS to attempt to identify fusional defects that may predispose to decompensation and to evaluate the prognosis after treatment for decompensated cases. Trans Am Ophthalmol Soc / 109 /

4 Siatkowski METHODS This study protocol was submitted in 2006 and subsequently approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center. The initial step was a diagnosis-sorted review of medical records of patients seen by this author from 1999 forward to identify potential subjects, followed by subject contact and assessment of potential interest in participation. Additional subjects were prospectively recruited as they were evaluated clinically. Eligible subjects were 18 years of age or older with a history of MFS and on chart review ocular misalignment of less than 8 PD, stereoacuity of no better than 60 arc seconds, Worth 4- dot fusion at near, and suppression of one eye at distance. The diagnosis of MFS and the patients prior ophthalmologic history were confirmed via review of prior optometric, ophthalmologic, and/or surgical records, patient and parental history, and examination of old photographs when available or pertinent. Subjects were considered decompensated if they had a chief complaint of acquired, bothersome binocular diplopia, with or without a change in their angle of strabismus. Stable subjects were those patients with MFS with no diplopia or other visual complaints, and no recent change in ocular alignment. Patients were excluded if they had ocular disease that produced a nonrefractive change in visual acuity by more than 1 Snellen line (eg, cataract, epiretinal membrane) or a neurologic condition that could affect ocular motility or fusional capacity (eg, brainstem stroke, multiple sclerosis). After discussion of the risks and benefits, and after obtaining informed consent, all subjects underwent a detailed record review, ophthalmologic examination, and orthoptic evaluation. Historical data obtained included the age at which decompensated patients became visually symptomatic; number of prior strabismus surgeries; history of glasses wear, patching, or other amblyopia therapy; treatment with orthoptic exercises; the age at which their original motility diagnosis occurred and was treated; and the original condition (infantile esotropia, esotropia with accommodative component, constant or intermittent exotropia, vertical strabismus, primary MFS, unknown). Patients spherical equivalent refraction and astigmatism status in each eye were recorded, as was the presence of anisometropia of more than 1 diopter (D) in either the spherical or cylindrical correction. Examination consisted of measurement of linear Snellen visual acuity in each eye, measurement of muscle balance at distance and near in the primary position by simultaneous and alternate prism cover tests, assessment of the presence of dissociated strabismus complex which in our cases was always dissociated vertical deviation (DVD) pattern strabismus, and ductions and versions. Sensory evaluation consisted of measurement of contour (Titmus test; Titmus Optical Company, Petersburg, Virginia) and random dot (Randot test; Titmus Optical Company, Petersburg, Virginia) stereoacuity; strength of Bangerter foil at which fixation preference switched; Worth 4-dot responses (constant or intermittent fusion, suppression of one eye or alternate suppression, diplopia, indeterminate); assessment of response to the 4-D base-out prism test (normal, suppression of one eye, alternate suppression); and response to the Bagolini glass test (NRC or ARC, with or without suppression). The following tests were performed on a synoptophore: measurement of torsional fusional amplitudes, subjective fusional responses using both simultaneous perception and fusion (partially similar image) slides, and assessment of retinal correspondence (NRC, harmonious vs unharmonious ARC, or complete suppression of one eye). Horizontal and vertical fusional amplitudes were also measured at both distance and near in free space. For the cross-sectional comparison of these two groups, and based on the type of data obtained for each variable, appropriate statistical analysis was performed comparing subjects with stable vs decompensated MFS. Fisher s exact test was used to compare proportions, and two-sample t-tests were used to compare means of interval level variables. Measurements made with the Titmus and Randot tests did not meet the distributional assumptions of the t-test and so for these variables the groups were compared with the Mann-Whitney nonparametric test. All P values were two-sided (two-tailed). Cumulative proportions of incident decompensated MFS cases were calculated with the Kaplan-Meier product-limit estimate method. Despite numerous tests of statistical significance evaluated in this study, no multiple comparison adjustment was applied. This was to prevent an increase in type II (beta) error, although there is the possibility of alpha inflation as a result. RESULTS From August 1, 1999, to July 31, 2009, this author evaluated a total of 12,079 individual patients (not patient visits) at the Dean McGee Eye Institute/Department of Ophthalmology, University of Oklahoma College of Medicine. Of these, 221 (1.84%) met criteria for diagnosis of MFS. Of these 221, 26 (11.8%) met criteria for the definition of decompensated MFS. (An additional 6 patients with prior MFS and an increase in their angle of strabismus were found but excluded from this study since they had no diplopia; including these, 14.5% of patients with MFS had a change in their motor or sensory status). Of the 26 patients with diplopia, 6 were excluded because they were under 18 years of age, 3 were excluded due to neurologic disease (2 cases of stroke and 1 case of myasthenia gravis), and 1 was excluded due to an overlying functional or nonphysiologic component to her responses. A total of 16 eligible adult subjects with decompensated MFS remained. Of these, 14 (87.5%) consented to be part of this study. Of these 14, 10 were evaluated and treated prospectively in their decompensated condition; 4 had been treated for decompensated MFS by this author prior to the start of the study. For these 4, retrospective data from chart review prior to treatment for decompensation was extracted. An additional 16 patients with stable MFS were randomly selected as controls, matched by age and sex as closely as possible. None of the subjects in the control group had undergone surgery for decompensated MFS; additionally, none of the subjects in either cohort in this study were related to one another. Because the patients who had been treated for decompensated MFS prior to the start of the study did not have complete data sets at the time they were in the decompensated state, statistical analysis was performed both with and without these 4 decompensated patients. Trans Am Ophthalmol Soc / 109 /

5 Decompensated Monofixation Syndrome The groups were strikingly similar with respect to baseline demographic and clinical characteristics (Table 1). There was no difference between stable and decompensated MFS patients with respect to age at study examination, glasses wear, history of patching or orthoptic exercises, or number of prior strabismus surgeries. There was no significant difference between the groups in interocular visual acuity difference, or in the presence or absence of amblyopia (with definitional cutoffs of 1, 2, or 3 or more lines difference between groups). The two groups were also similar with respect to the mean difference in refractive error between eyes, the prevalence of more than 1 D of spherical and cylindrical anisometropia, and the amount of astigmatism. (Additional analysis, not listed in Table 1, also showed no difference in proportion of eyes with cylinder axis >15 degrees from either 90 or 180 degrees). TABLE 1. HISTORICAL AND CLINICAL FEATURES OF PATIENTS WITH STABLE AND DECOMPENSATED MONOFIXATION SYNDROME CHARACTERISTICS DECOMPENSATED * STABLE P VALUE * Mean age (SD) 47.8 (15.9) / 45.3 (16.7) 37.4 (20.1).180/.259 Mean age in years at original diagnosis (SD) 21.5 (26.5) / 16.6 (23.5) 4.7 (4.0).076/.084 Glasses wear 9 (90%) / 13 (93%) 16 (100%).39/.47 Prior patching therapy 2 (20%) / 3 (21%) 5 (31%).44/.69 Prior orthoptic treatment 1 (10%) / 2 (14%) 4 (25%).34/.66 Number of prior strabismus surgeries.12/ (50%) / 8 (57%) 7 (44%) 1 1 (10%) / 1 (7%) 3 (19%) 2 1 (10%) / 2 (14%) 3 (19%) 3 3 (30%) / 3 (21%) 0 4 0/0 3 (19%) Mean interocular logmar acuity difference (SD) 0.09 (0.13) / 0.07 (0.11) 0.07 (0.14).77/.83 Presence of amblyopia.38/.38 1-line IOD 1 (10%) / 1 (7%) 3 (19%) 2-line IOD 1 (10%) / 1 (7%) 2 (13%) 3-line IOD 2 (20%) / 2 (14%) 1 (6%) Original diagnosis.63/.79 Infantile ET 5 (50%) / 5 (39%) 5 (31%) Accommodative ET 1 (10%) / 3 (23%) 5 (31%) XT or X(T) 1 (10%) / 2(15%) 1 (6%) Vertical 0/0 0 Primary 3 (30%) / 3 (23%) 4 (25%) Unknown 0/0 1 (6%) Mean SEQ interocular Refractive error difference (SD) 1.14(0.93) / 0.99(0.83) 0.61 (1.22).25/.33 Anisometropia >1 D 6 (60%) / 6 (43%) 2 (25%).11/.44 Mean (SD) of average cylinder (D) 0.86 (0.60) / 0.75 (0.57) 0.94 (1.06).84/0.56 Anisoastigmatism >1 D 2 (20%) / 2 (14%) 1 (6%).54/0.59 Age at onset decompensation symptoms (range) 37.5 / 38 (16-65) NA Mean years of stability prior to decompensation 23.1 / 26.5 NA Mean years of symptoms prior to diagnosis (range) 4.6 / 4.6 (0.5-15) NA D, diopters; ET, esotropia; IOD, interocular difference; NA, not applicable; SD, standard deviation; SEQ, spherical equivalent refractive error equivalent; XT, exotropia; X(T), intermittent exotropia. * Calculated without/with cases treated entirely prior to inception of study. Similarly, there was no difference between groups in the distribution of original diagnosis preceding the development of MFS; however, there was a trend for the decompensated MFS group to have received their original diagnosis and treatment much later than the stable group (21.5 vs 4.7 years [P=.076, two-sample t-test] for patients studied prospectively; 16.6 vs 4.7 years [P=.084, twosample t-test] including all decompensated patients). The mean age at onset of symptoms in the decompensated patients was 38 years (range, 16 to 65 years). Decompensated patients had been stable without symptoms for 23 to 26 years on average. Symptoms persisted for a mean of 4.6 years (range, 6 months to 15 years) prior to diagnosis of decompensated MFS. A few significant differences in motor findings between the groups were evident. Decompensated MFS patients were more likely than stable MFS patients to have a vertical deviation (50% vs 6%, P=.018/.012, Fisher s exact test), and the mean deviation of vertical strabismus tended to be larger in decompensated patients (1.1 PD vs 0.1 PD, P=.055/.025, two-sample t-test). There was a trend toward a larger distance angle of strabismus (irrespective of direction of deviation) among decompensated patients (P=.053/.004, two-sample t-test) and a larger angle of esotropia by alternate prism and cover testing in the decompensated group (10.9 PD for prospective cases and 17.7 PD for all Trans Am Ophthalmol Soc / 109 /

6 Siatkowski decompensated cases vs 6.89 PD for stable cases, P=.021/.008, two-sample t-test). There was a trend toward a larger esophoria at both near (P=.071/.069, two-sample t-test) and distance (P=.070./057, two-sample t-test) in decompensated patients, but the clinical significance was minimal, with mean differences only approximately 3 PD. Otherwise, stable and decompensated MFS patients did not differ with respect to the presence of DVD, ductional or versional abnormalities, pattern strabismus, and other aspects of horizontal strabismus (Table 2). TABLE 2. CLINICAL MOTOR FEATURES OF PATIENTS WITH DECOMPENSATED VERSUS STABLE MONOFIXATION SYNDROME CHARACTERISTICS DECOMPENSATED* STABLE P VALUE * Presence of vertical deviation 5 (50%) / 7 (50%) 1 (6%).018/.012 Presence of DVD 1 (10%) / 2 (14%) 3 (19%).50/.99 Full versions 7 (70%) / 10 (71%) 9 (56%).39/.47 Presence of pattern strabismus 0/0 0 Mean angle of strabismus (SD) Distance SPCT 5.9 (3.4) / 6.25 (4.1) 4.3 (3.3).25/.18 Distance APCT 8.5 (5.0) / 11.1 (6.6) 5.1 (3.6).053/.004 Near SPCT 6.4 (4.9) / 7.6 (7.2) 5.6 ( 4.5).34/.18 Near APCT 8.6 (5.6)11.4(9.6) 5.2 (4.6).10/.039 Vertical 1.1 (1.4) / 1.1 (1.5) 0.1 (.05).055/.025 Mean angle distance strabismus (SD) Esotropia SPCT 7.1(3.2) / 6.5(3.5) 6.44(2.4).63/.039 APCT 10.9(3.8) / 17.7(5.4) 6.89 (2.3).021/.008 Exotropia SPCT 2.5(2.1) / 6.3(6.8) 2.8 (2.2).90/.36 APCT 2.5(2.1) / 8.3(10.2) 4.8 (4.1).52/.54 Mean angle near strabismus (SD) Esotropia SPCT 6.5(5.1) / 5.9(5.8) 6.1 (3.5).71/.91 APCT 10.2(6.5) / 13.1(8.9) 6.0 (3.7).14/.043 Exotropia SPCT 7.3(3.1) / 11.8(9.2) 5.8 (6.2).71/.32 APCT 7.3(3.1)13.0(11.6) 7.3 (5.6).98/.41 Mean deviation, signed tropias Distance SPCT 5.0 (6.8) / 3.0 (7.3) 3.0 (4.6).33/.99 Distance APCT 7.9 (6.8) / 7.8 (11.2) 2.8 (5.7).055/.12 Near SCPT 1.9 (8.6) / 0.5 (11.1) 1.6 (6.3).93/.52 Near APCT 3.6 (10.0) / 4.1 (15.3) 1.5 (6.9).53/.55 Phorias (APCT-SPCT) Distance ET 3.7 (4.8) / 4.5 (5.0) 0.44 (1.3).070/.057 XT 0.0 (0.0) / 2.0 (3.5) 2.0 (4.0).54/.99 All 2.9 (4.5) / 3.8 (4.6) 1.0 (2.5).23/.091 Near ET 3.7 (4.3) / 4.3 (4.9) 0.5 (1.4).071/.069 XT 0 (0)/1.3 (2.5) 1.5 (3.0).44/.90 All 2.4 (3.8) / 3.5 (4.5) 0.8 (2.0).23/.072 APCT, alternate prism and cover test; DVD, dissociated vertical deviation; ET, esotropia; SD, standard deviation; SPCT, simultaneous prism and cover test; XT, exotropia. * Calculated without/with cases treated entirely prior to inception of study. Negative values indicate an esodeviation; positive values, an exodeviation. Sensory responses to various tests differed between groups (Table 3). Decompensated patients had significantly poorer convergence and divergence fusional amplitudes. Convergence amplitudes averaged 16.9 PD vs 6.4 PD (P=.001, two-sample t-test) at distance and 20.6 vs 8.1 PD (P=.004, two-sample t-test) at near. Mean divergence amplitudes were 9.9 PD vs 4.0 PD at distance (P=.049, two-sample t-test) and 11.3 PD vs 4.5 PD at near (P=.010, two-sample t-test). Vertical fusional amplitudes were similar between groups, but the decompensated patients had significantly larger cyclovertical amplitudes than the stable groups. Trans Am Ophthalmol Soc / 109 /

7 Decompensated Monofixation Syndrome TABLE 3. CLINICAL SENSORY FEATURES OF PATIENTS WITH DECOMPENSATED VERSUS STABLE MONOFIXATION SYNDROME CHARACTERISTICS DECOMPENSATED * (SD) STABLE (SD) P VALUE * Fusion amplitudes Distance (PD) BO 6.4 (5.2) 16.9 (8.7).001 BI 4.0 (3.4) 9.9 (7.5).049 BD 3.4 (3.9) 5.0 (3.6).40 BU 3.6 (4.1) 4.7 (3.2).54 Near (PD) BO 8.1 (8.0) 20.6 (10.4).004 BI 4.5 (3.3) 11.3 (10.8).10 BD 4.8 (3.6) 7.4 (6.5).41 BU 3.4 (3.0) 6.3 (5.90).30 Excyclovergence (degrees) 9.1 (2.7) 3.3 (1.5) <.001 Incyclovergence (degrees) 7.1 (4.3) 3.1 (1.9).041 Mean Bangerter strength 0.24 (0.40) 0.16 (0.22).58 Mean stereoacuity (arcsec) Titmus (range) 1700 (80-blind)/400 (80-blind) 400 (50-blind).59/.61 Measurable 7 (70%)/10 (71%) 13 (81%).64/.68 Randot (range) Blind (0-blind) 600 (100-blind).76 Measurable 4 (44%) 9 (56%).69 Worth 4-dot, near.56/.37 Fusion Constant 7 (70%)/10 (71%) 11 (69%) Intermittent 0/0 2 (13%) Suppression One eye 1 (10%)/1 (10%) 1 (7%) Alternate 1 (10%)/1 (10%) 2 (13%) Diplopia 1 (10%)/2 (14%) 0 Worth 4-dot, distance.046/.027 Fusion Constant 3 (30%)/3 (21%) 5 (31%) Intermittent 0/0 2 (13%) Suppression One eye 1 (10%)/2 (14%) 8 (50%) Alternate 3 (30%)/4 (29%) 3 (19%) Diplopia 3 (30%)/5 (36%) 0 Bagolini responses.23 No suppression 6 (75%) 7 (47%) Suppression 2 (25%) 8 (53%) Synoptophore fusion slides.49 Fusion 7 (70%) 12 (75%) No fusion 1 (10%) 3 (19%) Indeterminate 2 (20%) 1 (6%) Simultaneous perception slides.44 NRC 4 (40%) 9 (56%) Harmonious ARC 1 (10%) 3 (19%) Unharmonious ARC 4 (40%) 2 (13%) Total suppression 1 (10%) 2 (13%) ARC, anomalous retinal correspondence; BD, base down; BI, base in; BO, base out; BU, base up; NRC, normal retinal correspondence; PD, prism diopters; SD, standard deviation. * Calculated without/with cases treated entirely prior to inception of study. Mean excyclovergence amplitudes were 9.1 degrees in the decompensated group vs 3.3 degrees in the stable group (P<.001, twosample t-test); incyclovergence amplitudes were 7.1 degrees vs 3.1 degrees (P=.041, two-sample t-test). There were no significant differences in the density of Bangerter foil strength required to switch fixation or responses to Bagolini lens testing or amblyoscope testing with either fusion or simultaneous perception slides. Worth 4-dot responses at near were similar between decompensated and Trans Am Ophthalmol Soc / 109 /

8 Siatkowski stable patients, whereas at distance there was a greater tendency for stable patients to constantly suppress the same eye and for decompensated patients to report diplopia (P=.046/.027, Mann-Whitney test). Levels of both contour and random dot stereoacuity were similar between groups. Since the lowest level of stereoacuity testable on both the Titmus and Randot tests is 3000 arc seconds, data were analyzed in two ways. In the first analysis, patients who had no measurable stereoacuity on either test were assigned an arbitrary score of 5000 arc seconds, and data were analyzed with the Mann- Whitney rank sum test rather than the t-test. In the second analysis, the proportion of patients in each group who had no measurable stereoacuity on either test was evaluated. There was no significant difference between groups with either analysis, both including and excluding the cases with data prior to treatment. Table 4 shows the workup each decompensated patient underwent prior to the diagnosis. Among 14 patients, 5 neuroimaging studies and 1 orbital echogram were performed. Patients had a mean of 2.71 prior examinations and had received a mean of 2.57 prior pairs of glasses, including 5 patients with 4 or more examinations and 3 patients with 5 or more pairs of glasses. Only 1 patient among all 14 decompensated cases received the diagnosis of decompensated MFS on the first visit to a medical care provider. TABLE 4. PRIOR WORKUP AND MANAGEMENT OF PATIENTS WITH DECOMPENSATED MONOFIXATION SYNDROME PATIENT EVALUATIONS AND TESTS COST IN 2009 DOLLARS (CHARGE/MEDICARE ALLOWABLE) * 1 MRI, CT, orbital echography, 1 eye exam, 1 neuro exam $3155 / $ eye exams, 6 pairs glasses $1506 / $ MRI, 2 pairs glasses, 1 eye exam, 1 neuro exam $1607 / $ eye exam, 1 pair glasses $376 / $ MRI, edrophonium test, 4 eye, 1 neuro exam $2005 / $ eye exam, 2 pairs glasses $452 / $ eye exams, 10 pairs glasses $2260 / $ No prior workup 0 9 MRI, 3 neuro exams, 1 eye exam $1565 / $ eye exams, 2 pairs glasses $752 / $ eye exams, 2 pairs glasses $1252 / $ eye exams, 2 pairs glasses $1002 / $ eye exams, 5 pairs glasses $1380 / $ eye exams, 4 pairs glasses $1754 / $ Mean $1168 / $797 CT, computed tomography; MRI, magnetic resonance imaging. * 2009 Dean McGee Eye Institute charges and Oklahoma Medicare reimbursements of: Level III evaluation, $105/$56.85; Level IV evaluation, $155/$85.76; sensorimotor exam, $95/$49.17; MRI brain with/without gadolinium, $1000/$545.06; CT head with/without contrast, $450/$243.34; intravenous edrophonium chloride test, $90/$37.35; prism glasses, $126/$126. Table 5 provides selected individual clinical details on the 14 decompensated patients. Most patients had a prior diagnosis of esotropia (5 infantile and 3 with an accommodative component). Three had primary MFS and 2 had intermittent exotropia, presumably monofixational in nature. The mean age (and range) at onset of decompensation was 39.6 years (range, years) for patients who had infantile esotropia, 43.3 years (range, years) for those with an accommodative component to their esotropia, 45 years (range, years) for the primary monofixators, and 18 and 53 years for the 2 exotropes. One patient s original diagnosis could not be definitively determined from old record review, although it was clear that he had some type of esotropia. All but 1 decompensated patient underwent treatment. Six had strabismus surgery, 4 were treated with orthoptic exercises, 3 were treated with prisms, and 2 were prescribed a change in glasses without prisms. One patient was treated with Bangerter foil occlusion. Among the patients who were treated surgically, a monofixational angle of strabismus was achieved in all cases postoperatively, with a follow-up of at least 15 months in each case. However, contour stereopsis improved (defined as at least a 2-octave increase on the Titmus test) in only 1 of these patients postoperatively; an improvement in stereopsis was noted in 1 additional patient who was treated with orthoptic fusional vergence exercises. Prior to treatment, as part of our diagnostic criteria, all patients suffered diplopia. After treatment, 77% of patients had an improvement in their symptoms, with 9 patients being diplopia-free and 1 patient who had had prior constant diplopia experiencing only intermittent diplopia. Two patients who before treatment had constant diplopia and 1 who had intermittent symptoms remained unchanged. Table 6 provides additional clinical information on the decompensated patients, including the number of years each patient had been stable prior to onset of symptoms and individual horizontal and torsional fusional amplitudes, where data is available. Convergence and divergence amplitudes at distance and near were measured in free space, whereas cyclofusional amplitudes were assessed on the synoptophore using a target that subtended a visual angle of 9 degrees horizontally and vertically. Further details regarding these data will be addressed in the next section. Trans Am Ophthalmol Soc / 109 /

9 Decompensated Monofixation Syndrome TABLE 5. TREATMENT AND OUTCOME OF PATIENTS WITH DECOMPENSATED MONOFIXATION SYNDROME PATIENT ORIGINAL DIAGNOSIS/AGE AT TREATMENT ANGLE OF STRABISMUS * STEREOPSIS (ARCSEC) DIPLOPIA DECOMPENSATION Pre Post Pre Post Pre Post 1 Infantile ET/16 declined rx ET 12 NA NMS NA int NA 2 Primary/47 prism, orth ET 8 LH const const 3 Infantile ET/53 prism, orth XT 10 ortho NMS NMS int none 4 Primary/65 prism RHT 4 RHT const none 5 Infantile ET/38 EMS ET 14 ET const int 6 Accommodative ET/37 EMS ET 10 ortho int none 7 Infantile ET/46 EMS ET 14 ET 4 NMS NMS int none 8 Infantile ET/45 Bang XT 4 XT 4 NMS NMS int int 9 Primary/23 orth ET 14 ET const const 10 X(T)/53 orth orth XT 8 X const none 11 Accommodative ET/30 glasses ET 14 ET int none 12 X(T)/18 EMS, glasses XT 30 X int none 13 Accommodative ET EMS ET 14 ET const none 14 ET/46 EMS ET 30 ET 8 NMS NMS int none Summary 100% with MFS angle of strabismus 2 of 13 with 2 octave difference 9 of 13, none2 of 13, int2 of 13, const77% improved Bang, Bangeter filter; const, constant; EMS, eye muscle surgery; ET, esotropia; int, intermittent; LH, left hyperphoria; NA, not applicable; NMS, no measurable stereopsis; orth, orthoptic exercises; ortho, orthotropic; RHT, right hypertropia; X, exophoria; X(T), intermittent exotropia. * Measurements represent results of alternate prism and cover testing. TABLE 6. FUSIONAL AMPLITUDES OF INDIVIDUAL PATIENTS WITH DECOMPENSATED MONOFIXATION SYNDROME FUSIONAL AMPLITUDES PATIENT CONVERGENCE DISTANCE/NEAR(PD) DIVERGENCE DISTANCE/NEAR(PD) EXCYCLOVERGENCE (DEGREES) 1 1/1 1/ /4 no data /10 6/ /4 6/ /6 8/ /12 8/6 No data No data 7 18/12 8/ /1 2/ /14 No data No data No data 10 2/2 2/ No data No data No data No data 12 No data No data No data No data 13 No data No data No data No data 14 No data No data No data No data PD, prism diopters. INCYCLOVERGENCE (DEGREES) Trans Am Ophthalmol Soc / 109 /

10 Siatkowski DISCUSSION Although occurring in a minority of cases, loss of stability of motor and/or sensory status in patients with previously static and asymptomatic MFS constitutes an important clinical entity. In this series, a change in either the angle of strabismus and/or the onset of diplopia occurred in 32 of 221 (14.5%) of all MFS patients (adults and children) seen by a single physician over a decade. Sixteen adult patients (7.2%) with MFS experienced new-onset binocular diplopia during this period. These patients represent 0.13% to 0.27% of all patients seen in an academic practice of pediatric ophthalmology, strabismus, and neuro-ophthalmology. Although the denominator and time period are unclear, these data are not markedly disparate from the report by Hunt and Keech 36 of 29 deteriorated MFS patients, presumably seen over several decades at the University of Iowa, and the calculation of Arthur and colleagues 31 that 26% of MFS patients developed a decompensation over a mean 17.5-year period. In the current study, all cases of stable MFS patients were diagnosed prior to age 18; therefore, it makes good sense to calculate risk of decompensation in adults with MFS (aged 18 years or older) relative to age. Analyzing all of the adults with MFS (age range, years) evaluated over the 10-year period of this study, one can derive a Kaplan-Meier analysis of the rate of cumulative decompensation over time (Figure). (The 109 MFS patients seen only as children cannot contribute meaningfully to the risk estimate because they have not had a chance to decompensate yet and are not included in the Kaplan-Meier curve.) Additional data regarding the decompensation rates is available in Table 7. This curve suggests that the risk of decompensation is modest (<5%) for individuals under 30 years of age but increases linearly through the sixth decade of life to involve 20% to 30% of MFS cases. For older ages, the study s sample size is relatively small, but the data suggest that for every decade of life beyond age 40, an additional 10% of previously stable patients with MFS decompensate. FIGURE Kaplan-Meier curve of rate of decompensation for 112 adults with monofixation syndrome seen over a 10-year period. Lang 37 estimated the prevalence of microtropia to be approximately 1% in the general population, similar to the estimated prevalence of MFS. 25 As noted in the Introduction section, heredity may play a role in the etiology of MFS, with 9% of first-degree relatives of patients with infantile esotropia demonstrating MFS. 25 Cantolino and von Noorden 38 also found microtropia in 25% of first-degree relatives in a series of 20 patients with the same condition, and Lang 39 noted a higher incidence of microtropia in monozygotic twins with ocular motility disorders. Cibis 40 reported microtropia in almost half of all treated esotropes and one-quarter of treated exotropes in a series of over 500 consecutive patients in his practice. Excluding twin cases and disregarding the clinical overlap in some cases of microtropia vs MFS, up to 3.2 million persons in the United States may have MFS. According to the analysis of Arthur and colleagues, 31 26% of patients with MFS experience a worsening of alignment over a 17.5-year period. Of our patients with worsening alignment, 62% experienced diplopia, and in the series by Hunt and Keech, 36 29% had double vision. Averaging these rates of diplopia and assuming a linear rate of decompensation per annum, slightly over 20,000 patients annually in this country would present with diplopia following decompensation of a previously stable monofixational state. Trans Am Ophthalmol Soc / 109 /

11 Decompensated Monofixation Syndrome TABLE 7. CUMULATIVE PROPORTION OF PATIENTS WITH DECOMPENSATION OF MONOFIXATION SYNDROME WITH AGE IN DECADES AGE PROPORTION DECOMPENSATED (SE) NUMBER OF PATIENTS REMAINING STABLE % (1.2%) % (2.1%) % (3.8%) % (5.9%) % (7.1%) % (9.7%) 6 SE, standard error. There are approximately 1,000 practicing pediatric ophthalmologists and approximately 400 practicing neuro-ophthalmologists in the United States. Assuming that 75% of decompensated diplopic patients would eventually be evaluated by a pediatric ophthalmologist, strabismologist, or neuro-ophthalmologist, then each such provider would see on average about 11 new such patients annually. Using the numbers provided in this study (7% of adults with MFS decompensating with diplopia over a decade, and 10% per decade new compensations after age 40), along with the assumptions discussed above, would result in a figure of about 12 new decompensated MFS patients annually per pediatric ophthalmologist, strabismologist, or neuro-ophthalmologist in the United States. The results of these two calculations are remarkably similar; although these figures may seem higher than what occurs in practice, they are certainly plausible, especially since the prevalence data are likely inflated given the selection bias of patients seen in a tertiary care, university setting. Adults with diplopia are commonly evaluated in clinical practice, and many cases in which there is no neurologic or orbital explanation for symptoms are diagnosed as decompensated phorias or long-standing strabismus ; it is likely that a more detailed analysis of some proportion of these patients would support a diagnosis of decompensated MFS. Additionally, there remains the possibility that a relatively large number of patients aged 40 or older with decompensated MFS are either being seen by primary care vision providers (comprehensive ophthalmologists and optometrists) or simply not seeking care at all. The MFS patients in our study, by definition, met the Parks criteria for diagnosis, 21 but their sensorial adaptations are similar to others throughout the world who have reported on MFS, microtropia, and similar conditions since his AOS thesis was published The question remains, What causes these patients who have been stable and asymptomatic, generally for decades, to decompensate? Kushner 46 has written eloquently of the development of diplopia in adults with long-standing strabismus who had been asymptomatic for years. In his algorithm, the majority of such patients with new binocular diplopia have experienced a change in their angle of strabismus. The second most common cause was a change in refractive need or correction, that is, onset of presbyopia, latent hyperopia in an accommodative esotrope, or fixation switch diplopia due to change in acuity in the dominant eye. His series reported a success rate of 84% after changing optical correction and/or performing strabismus surgery. However, it is unclear what proportion of the patients in this study had decompensated MFS. Only 2 of our decompensated patients were treated with a change in glasses prescription (1 with accommodative esotropia and 1 with intermittent exotropia who also underwent surgery), and both were successful. Thirteen of our patients with MFS did experience an increase in their angle of strabismus (although only 6 were treated surgically); of the 12 who were treated, 10 (83%) experienced an improvement in symptoms. Pratt-Johnson and Tillson 47 have commented on the possibility of unstable or variable suppression patterns in patients with strabismus. Their work clearly supports the contention of Parks of a stable, small central scotoma and NRC in patients with MFS. Hence it is unlikely that any type of variable hemiretinal suppression (like that which can operate in patients with larger angles of strabismus and ARC) plays a role in the decompensation of MFS patients. Arnoldi 35 found the presence of stereopsis to be protective against motor deterioration in patients with MFS, but in this series and in this author s work in this area, neither the presence nor the degree of stereopsis was associated with stability in monofixators. Hahn and colleagues 48 found higher degrees of stereopsis in patients with a later onset of strabismus who eventually developed MFS, implying a shorter period of misalignment prior to treatment. This study found an important trend in this regard, namely, that stable adult patients had been initially diagnosed and treated, on average, over a decade earlier than decompensated adults with MFS. Although not statistically significant, this difference is likely clinically important and represents a real trend, since the mean age of stable and decompensated subjects was similar; additionally, there is no concern for selection bias, since age at initial diagnosis was not part of the selection criteria. Thus, minimizing the period of initial ocular misalignment by treating patients more promptly probably confers the benefit of a higher likelihood of stability through adulthood once MFS is established. There was no difference between stable and decompensated MFS patients in the antecedent strabismic conditions prior to the development of MFS or in the prevalence of primary monofixators between groups. Like most other series, 21,31,35 this study found esotropia, particularly infantile esotropia, to be the most common original condition in adults with MFS. The development of a stable, monofixational state has been reported in 25% to 50% of patients after surgery for infantile esotropia, although its incidence is lower in children with myopia. 52 Esotropia with an accommodative component was our next most common diagnosis prior to development of MFS. MFS is a common outcome in such patients, with bifixation developing in only a minority after treatment. 53,54 The next most common condition among this series of patients with decompensated disease was primary, idiopathic MFS, Trans Am Ophthalmol Soc / 109 /